U.S. patent application number 13/666127 was filed with the patent office on 2014-05-01 for system and apparatus for multimodality-compatible high-quality intravital radionuclide imaging.
This patent application is currently assigned to Kuangyu Shi. The applicant listed for this patent is Zhen Liu, Markus Schwaiger, Kuangyu Shi, Sibylle I. Ziegler. Invention is credited to Zhen Liu, Markus Schwaiger, Kuangyu Shi, Sibylle I. Ziegler.
Application Number | 20140121493 13/666127 |
Document ID | / |
Family ID | 50547912 |
Filed Date | 2014-05-01 |
United States Patent
Application |
20140121493 |
Kind Code |
A1 |
Shi; Kuangyu ; et
al. |
May 1, 2014 |
System and Apparatus for Multimodality-compatible High-quality
Intravital Radionuclide Imaging
Abstract
The present invention discloses an imaging system and apparatus
to obtain high-resolution low-noise intravital radionuclide imaging
based on transparent window chamber. This imaging system is
dedicated to preclinical research. It comprises a transparent
window chamber, in particular a dorsal skin window chamber or a
cranial chamber or an ear chamber or a spine cord chamber on a
living animal, and a high-quality radionuclide imaging camera for
the imaging of positron or electron. The apparatus is compatible
with multimodality imaging, in particular magnetic resonance
imaging (MRI), microscopy imaging including fluorescence
microscopy, phosphorescence microscopy and two-photon
microscopy.
Inventors: |
Shi; Kuangyu; (Munich,
DE) ; Liu; Zhen; (Munich, DE) ; Ziegler;
Sibylle I.; (Munich, DE) ; Schwaiger; Markus;
(Munich, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Shi; Kuangyu
Liu; Zhen
Ziegler; Sibylle I.
Schwaiger; Markus |
Munich
Munich
Munich
Munich |
|
DE
DE
DE
DE |
|
|
Assignee: |
Shi; Kuangyu
Munich
DE
|
Family ID: |
50547912 |
Appl. No.: |
13/666127 |
Filed: |
November 1, 2012 |
Current U.S.
Class: |
600/411 |
Current CPC
Class: |
A61B 5/0035 20130101;
A61B 5/0555 20130101; A61B 6/4417 20130101; A61M 2250/00 20130101;
A61B 6/508 20130101; A61B 5/0068 20130101; A61B 6/501 20130101;
A61B 5/4848 20130101; A61B 5/0071 20130101; A61B 5/0042 20130101;
A61B 6/037 20130101; A61B 6/425 20130101; A61D 3/00 20130101; A61M
16/01 20130101 |
Class at
Publication: |
600/411 |
International
Class: |
A61B 6/00 20060101
A61B006/00; A61M 16/01 20060101 A61M016/01; A61B 6/03 20060101
A61B006/03; A61B 6/04 20060101 A61B006/04; A61B 5/055 20060101
A61B005/055; A61B 5/00 20060101 A61B005/00 |
Claims
1. A transparent window chamber apparatus for multimodal intravital
imaging is compatible with a direct high-quality in vivo
radionuclide imaging camera, magnetic resonance imaging (MRI) and
optical microscopy including fluorescence, phosphorescence,
confocal or multi-photon microscopy.
2. The transparent window chamber according to claim 1 refers to an
in vivo tissue observation window on animals. In particular, it
refers to a dorsal skin window chamber, or a cranial chamber, or a
hamster-cheek-pouch-window or a spine cord chamber.
3. The geometry of the transparent window chamber according to
claim 1 and 2 is shaped to allow the insertion of the imaging
detector of the radionuclide imaging camera, the placement of MRI
surface coils and the positioning on a microscope. The chamber is
fabricated with both biocompatible and MRI-compatible material.
4. The attachment of the transparent window chamber according to
claim 1 to the tissue has minimal invasiveness. In particular, the
screws for the fixation of the plates of the transparent window
chamber do not penetrate the tissues.
5. The transparent window chamber according to claim 1-3 fix the
imaging parts of different imaging modalities mechanically to allow
direct precise co-registration of the obtained images from
different sources at different times. In particular, it has
fixation pins to fix the radionuclide imaging camera, MRI surface
coils and microscopes.
6. The radionuclide imaging camera according to claim 1, which
detects the signal of positron or electron, images the tissue
object exclusively with the camera itself. It does not need any
functional material between the camera and the imaging object to
support the imaging procedure. The radionuclide imaging camera
comprises an integrated imaging detector and a reading out circuit.
In particular, the camera consists of a silicon-pixel detector and
a single pixel readout circuit.
7. The geometry of the radionuclide imaging camera according to
claims 1 and 6 is shaped to fit with the geometry of the
transparent window chamber according to claim 1 and the imaging
object. In particular, the detector of the camera is shaped to
protrude from the surrounding surfaces with at least more than 1 mm
distance to fit with the observation window.
Description
[0001] The present invention discloses an imaging system and
apparatus to obtain high-resolution low-noise intravital
radionuclide imaging based on transparent window chamber. This
imaging system is dedicated to preclinical research. It comprises a
transparent window chamber, in particular a dorsal skin window
chamber; cranial chamber, ear chamber or spine cord chamber on a
living animal and a high-quality radionuclide imaging camera for
the imaging of positron or electron. The apparatus is compatible
with multimodality imaging, in particular magnetic resonance
imaging (MRI), microscopy imaging including fluorescence
microscopy, phosphorescence microscopy and two-photon
microscopy.
[0002] The system of the present invention enables a reliable link
between macroscopic imaging and microscopic physiological
measurements. It allows high quality radionuclide imaging, high
compatibility with multiple imaging modalities, precise
co-registration of images obtained from different sources at
different times and intact longitudinal multimodal observation.
Thus the present invention can assist the validation and
development of pharmaceutical, imaging, diagnostic and therapeutic
techniques and strategies.
[0003] In contrast to conventional anatomical imaging such as CT or
MRI, molecular imaging extends the clinical frontline to
fundamental molecular pathways in organisms noninvasively, which
supports the individualization of healthcare. Among all the
molecular imaging modalities, radionuclide imaging such as positron
emission tomography (PET) or single photon emission computed
tomography (SPECT) are most widely used in clinical practice due to
their high sensitivity of physiological differences and have shown
enormous clinical value for example in early detection of cancer,
staging, localization and therapy prognosis.
[0004] Radionuclide imaging is achieved through injection of
radiolabeled molecular biomarkers, which generate contrast between
normal and abnormal tissues according to their different metabolic
properties of the injected biomarker. Various biomarkers have been
developed for the detection of different physiological functions
such as glycolysis (e.g. [18F]FDG, 99mTc-HMPAO), perfusion (e.g.
[13N]Ammonia, 99mTc-tetrofosmin), hypoxia (e.g. [18F]Fmiso),
proliferation (e.g. [18F]FLT) and so on.
[0005] The radioactive signals emitted from the radiolabeled
biomarkers can be detected by radiation cameras (Scintigraphy),
SPECT for single photon emitters or coincidence detectors (PET) for
positron emitters.
[0006] After injection into the body, molecular biomarkers are
delivered through macro- and microcirculatory system into tissues
and then get either metabolized in the target area or cleared out.
This complex procedure causes the acquired image to be influenced
by many confounding factors, such as vascular delivery,
interstitial transport and renal clearance. The interpretation of
molecular imaging towards characteristics of the tumor
microenvironment is therefore not straightforward.
[0007] For pharmaceutical development of new imaging biomarker or
the application of clinical diagnosis and therapy planning, the
assessment and validation of molecular imaging and its evaluation
methods is necessary.
[0008] The assessment of molecular images requires a reliable link
from macroscopic imaging to microscopic measurements. However, such
a reliable link is not straightforward.
[0009] Conventionally, tumors need to be resected after animal
scarification and be cut into sections for the investigation by
microscopy. Although these in vitro methods have been widely used
in various applications, they are destructive and have limited
ability to provide insight into in vivo dynamics. The inconsistency
between in vivo and in vitro does not meet the requirements for
clinical applications such as biologically guided radiotherapy.
[0010] Furthermore, there exists a huge difference between typical
preclinical and clinical molecular images (.about.mm) and
microscopic measurements (.about..mu.m). The current preclinical
PET can reach a resolution of approximately 1 mm while the
preclinical SPECT can achieve 0.4 mm resolution for small animals.
The measured signal in an imaging element is an integration of the
signal over a relatively large scale of heterogeneous tumor
microenvironment, which makes the validation of molecular imaging
even more difficult.
[0011] The resolution of current radionuclide imaging devices is
relatively low compared to morphological imaging modalities. For
preclinical research of radionuclide imaging, high resolution is
preferred.
[0012] Another problem for a reliable link from macro to micro is
the co-registration of images. It is very hard to find useful
landmarks or similarities between the images with such a huge
resolution difference and typical co-registration algorithms are
not applicable here. Also, the complicated preparation procedure of
the histology sections introduces lots of distortions, thus it is
almost impossible to localize the physiological features precisely
in conventional imaging methods.
[0013] As the evolving of combined imaging modalities, such as
PET/CT, PET/MRI, multimodal imaging is increasingly available in
clinical practice. Corresponding multimodal quantitative analysis
strategies is desired to assist the improvement of cancer diagnosis
and therapy planning.
[0014] One major challenge for multimodality imaging is the
co-registration between images obtained at different time, with
different procedures and of different resolution.
[0015] From Cho, H., Ackerstaff, E., Carlin, S. et al.:
"Noninvasive multimodality imaging of the tumor microenvironment:
registered dynamic magnetic resonance imaging and positron emission
tomography studies of a preclinical tumor model of tumor hypoxia.
Neoplasia, 11 (2009) 247-59 it is known that fiducial markers can
be inserted into tumor to assist the co-registration of MRI and PET
images. In addition, immobilization foams need to be applied to the
animal to fix the position and gesture. The procedure is
destructive and not suitable for longitudinal observation. The
registration error is still relatively large compared with the
microscopic features.
[0016] Transparent window chamber is an effective tissue
observation apparatus for intravital imaging. It sets up observable
tissue microenvironment between or behind a fixed transparent
window on an intact animal, which enables in-depth longitudinal
observation of tissue physiologies.
[0017] Transparent window chamber can be generally classified into
two categories based on tissue preparations: chronic window chamber
and acute window chamber. Chronic window chamber allows continuous
noninvasive, long-term monitoring of tissue pathologies. Typical
examples are ear chamber, dorsal skinfold chamber, cranial chamber,
hamster-cheek-pouch-window and spine cord chamber. Acute window
chamber allows the observation of orthotopic tumors. However it
does not support repeated or long-term observations. Typical acute
window chamber includes hamster cheek pouch, mesentery, liver or
pancreas chamber.
[0018] Intravital microscopy can be applied to transparent window
chamber to obtain intact in vivo imaging of physiological features.
In particular, the intravital microscopy includes fluorescence
microscopy, phosphorescence lifetime imaging, confocal laser
scanning microscopy and multi-photon microscopy.
[0019] Transparent window chamber has been applied in many studies
of various purposes, such as microcirculation, angiogenesis,
hypoxia and molecular dynamics and therapeutic interactions. In
vivo tissue morphological and metabolic characteristics like
acidity, oxygen tension can be obtained on from intravital imaging
on transparent window chamber.
[0020] US 2004/0151666 A1 discloses a rodent mammary transparent
window chamber for intravital microscopy of orthotopic breast
cancer. It enables the investigation of the cellular behavior of
implanted tumor cells in an orthotopic environment and to observe
the earliest events during angiogenesis.
[0021] US 2004/0043462 A1 discloses a transparent window chamber
for in vivo delivery of an active agent, which includes therapeutic
and screening methods for in vivo screening of angiogenesis and/or
tumor growth modulating agents.
[0022] US 2012/0035444 A1 discloses in vivo drug screening systems
based on transparent window chamber.
[0023] Gaustad, J. V., Brurberg, K. G., Simonsen, T. G., et al.:
"Tumor vascularity assessed by magnetic resonance imaging and
intravital microscopy imaging." Neoplasia, 10 (2008) 354-62
discloses a method to combine dynamic contrast enhanced MRI and
intravital microscopy imaging and to validate the blood flow
estimation of dynamic contrast enhanced MRI based on fluorescence
measurement with intravital microscopy.
[0024] Although transparent window chamber has advantages for
intravital imaging in revealing underlying tissue pathologies, it
is in general not easy to directly apply them in the research of
radionuclide imaging. One limitation for that purpose is the low
resolution of current PET or SPECT. It is almost impossible to
obtain a sufficient image of a surface tissue.
[0025] Most radiolabeled tracers of PET or SPECT emit positrons or
electrons. Imaging positron or electrons directly has the potential
to reach a resolution of microscopic level such autoradiography.
However, positron or electron has limited penetration either in air
or body. A direct imaging device of positron and electron needs to
contact the imaging object as close as possible.
[0026] Liu, Z, Chen, L, Barber, S., et al.: "Direct positron and
electron imaging of tumor metabolism and angiogenesis in a mouse
dorsal skin window chamber model," 59th Annual Meeting of the
Society of Nuclear Medicine, Miami, Fla., June, 2012 discloses a
high-resolution and high-sensitivity imaging system for direct
imaging of positrons or electrons on transparent window chamber for
in vivo studies of the tumor microenvironment. It needs an
ultrathin phosphor film to be placed between the investigated
tissue and a lens-coupled CCD camera to image the scintillation
light excited by a positron/electron-emitting object. This method
needs additional scintillation material between the camera and the
tissue. Although the phosphor film can be fit into a conventional
window chamber and enable the imaging of positron and electron
within the observation window. However the imaging of the
scintillation light from the phosphor film is easy to be influenced
by noise.
[0027] From Russo, P., Lauria, A., Mettivier, G. et al.: "18F-FDG
positron autoradiography with a particle counting silicon pixel
detector." Phys Med Biol, 53 (2008) 6227-43 and Mettivier, G.,
Montesi, M. C. and Russo, P.: "Digital autoradiography with a
Medipix2 hybrid silicon pixel detector." Nuclear Science, IEEE
Transactions on, 52 (2005) 46-50 it is know that a high-quality
positron or electron imaging can be achieved with silicon pixel
detector, which can read the incident particle energy deposited in
silicon detector directly using single pixel readout circuit. Thus
it has high signal to noise ratio compared to scintillation based
positron imaging. It has also high sensitivity and high
spatiotemporal resolution. The spatial resolution can reach 230
.mu.m and for positron and 55 .mu.m for electron. The temporal
resolution can reach within 0.1 second. It is also less sensitive
to gamma rays.
[0028] A layer of protection foil (e.g. Aluminum, Mylar) is usually
placed on top of the detector to protect the detector against
scratch and to filter out visible light.
[0029] The application of this radionuclide imaging camera with
silicon pixel detector was restricted with ex vivo tissue sections
or easily accessible in vivo objects. It was not possible to
directly extend it for the imaging on conventional transparent
window chamber. First, the geometry of the silicon detector did not
fit with the window geometry of the conventional transparent window
chamber. Second, the silicon detector protruded only very tiny from
the camera surface (<0.5 mm) and the thickness of the chamber
was relatively large for the conventional window chamber (>2
mm). Thus the silicon detector of the radionuclide imaging camera
cannot be inserted enough deep into a conventional window chamber
to get sufficient close contact with the tissue. Without a close
interaction with the imaging object, the resolution of the positron
or electron imaging is very small. A 100 .mu.m air gap will lead to
a reduction of resolution for approximately 100 .mu.m.
[0030] The apparatus of the present invention consists of three
modules: 1) transparent window chamber, 2) radionuclide imaging
camera and 3) supporting parts for multi-modality imaging.
[0031] The transparent window chamber in the present invention is
implanted in an animal, in particular a mouse or a rat. For
example, a dorsal skin window chamber can be implanted by removing
one layer of skin within the observation window of one side of the
chamber. A cranial window chamber can be implanted by removing the
skin and bone of a region on top of the skull to generate an
observation window area. Tumors can be transplanted into the
remaining tissue after the window chamber implantation.
[0032] The transparent window chamber in the present invention is
compatible with multimodal intravital imaging. In particular it is
compatible with a direct high-quality in vivo radionuclide imaging
camera, magnetic resonance imaging (MRI) and optical microscopy
including fluorescence, phosphorescence, confocal or multi-photon
microscopy.
[0033] The geometry of the transparent window chamber in the
present invention is shaped to allow the insertion of the imaging
detector of the radionuclide imaging camera, the placement of MRI
surface coils and the observation using microscope. In particular
the current observation window is relatively large and
square-shaped, which allows the insertion of typical square-shaped
detectors of radionuclide imaging cameras.
[0034] The transparent window chamber in the present invention has
dedicated slots to fix the imaging parts mechanically to allow a
precise co-registration of the obtained images. In particular it
has fixation pins with threads to fix different imaging parts and
allows direct co-registration of the obtained images.
[0035] The transparent window chamber in the present invention is
fabricated with both biocompatible and MRI-compatible material to
allow the application in animal and the imaging in MRI.
[0036] The thickness of the transparent window chamber in the
present invention is reduced to be as less as possible to allow a
close interaction between the detector and the tissue. In
particular, it is less than 1.5 mm.
[0037] The slots of fixation screws of the transparent window
chamber in the present invention locate on side of the transparent
window chamber and the screws do not penetrate the tissues, which
can minimize the invasiveness to the animal.
[0038] The transparent window chamber in the present invention can
be specified as in vivo observation window on animals; in
particular dorsal skin window chamber, cranial chamber,
hamster-cheek-pouch-window and spine cord chamber spiral
chamber.
[0039] The second part of the present invention is a direct
radionuclide imaging camera, which images the signal of positron or
electron exclusively with the camera itself. It does not need any
functional material outside the camera to support the imaging
procedure. In particular, the camera consists of a silicon-pixel
detector and a single-pixel counting readout circuit.
[0040] The geometry of the radionuclide imaging camera in the
present invention is shaped to fit with the geometry of the
transparent window chamber. In particular, additional material is
added between the detector and the camera board to allow enough
protruding of the detector from the surrounding surfaces. This
ensures a close contact of the detector to the investigating tissue
and allows a high-resolution direct imaging of the positrons or
electrons emitted by the tissue.
[0041] The third module of this apparatus is supporting parts for
compatibility with multimodality imaging. This includes 1)
functional supporting parts such as surface coils for MRI imaging,
2) positioning and immobilization parts such as anesthesia tube,
fixation pins, fixation of surface coils and 3) other assistance
parts such as magnetic shielding, fixation of glass slides,
catheters, and cables.
[0042] A surface coil can be attached to the transparent window
chamber to allow high-resolution MRI imaging. This surface coil
assures high sensitivity and B1 homogeneity and it is fixed to the
transparent window chamber mechanically.
[0043] The anesthesia tube of the present invention supports the
anesthesia of the animal and the positioning of the imaging
devices. The anesthesia tube consists of two parts, one base part
with anesthesia gas connectors and one cover with slots hosting the
placement of the transparent window chamber.
[0044] The fixation pins on the transparent window chamber of the
present invention is another example of immobilization parts, which
serves as the reference points for the direct co-registration of
images from multiple imaging modalities.
DESCRIPTION OF THE DRAWINGS
[0045] FIG. 1 is a sketch of an example system of the present
invention. It comprises a specialized transparent window chamber,
an adapted radionuclide imaging camera, glass slides to cover the
tissues within the observation window, fixation for glass slides
and supporting parts for multi-modality imaging such as animal
anesthesia tube, MRI surface coils, fixation of surface coils and
so on.
[0046] FIG. 2 shows an example of a dorsal skin transparent window
chamber of the present invention. It comprises the main body 1, an
observation window 2 to allow the insertion of the detector of the
radionuclide imaging camera, an assisting window 3 to allow the
insertion of other obligatory non-imaging parts of the radionuclide
imaging camera, four fixation pins with threads 4 to allow the
fixation of the transparent window chamber with other parts, a
series of suture holes 5 to allow the binding of sutures with the
tissues for the fixation of the transparent window chamber, screw
holes 6 for the fixation of the plates of the transparent window
chamber with screws, assistance excavation 7 to allow the fit with
other small protruding details on the camera surface and side wing
8 to protect the dorsal skin window chamber against tilting.
[0047] FIG. 3 shows an example of the fixation of glass slide for
the transparent window chamber of the present invention. It
comprises the main body of this fixation part 1, four holes 2 for
the insertion of fixation pins of the transparent window chamber,
protrusion 3 for the insertion into the observation window to fix
the glass slide. After the chamber implantation, the subcutaneous
tissue will be covered by a glass slide, which will be fixed using
this part. An observation window 4 above the glass slide allows the
monitoring of the tumor growth within the chamber. During the
imaging procedure, the glass slide and this fixation will be
detached from the chamber.
[0048] FIG. 4 shows an example of the fixation of MRI surface coil
for the transparent window chamber of the present invention. It
comprises the main body of this fixation part 1 with an observation
window 2 in the middle, two slots 3 to host the MRI surface coil
and four holes 4 for the insertion of fixation pins of the
transparent window chamber.
[0049] FIG. 5 shows an example of the anesthesia tube for the
animal, in particular a mouse or a rat. It comprises a base 1 of
the anesthesia tube and the corresponding cover 2. The base 1 is a
half tube for the placement of the animal. It consists of a
connector 6 for anesthesia gas including a gas inlet 7 and a gas
outlet 8. The edge 4 of the cover 2 can be stuck into the slots 5
of the base 1. On the top of the cover 1 exists a slot 3 hosting
the placement of the transparent window chamber in the anesthesia
tube.
[0050] FIG. 6 shows another example of the system for cranial
window chamber of the present invention. The cranial chamber 1
comprises an observation window 2 to allow the insertion of the
detector of the radionuclide imaging camera, an assisting window 3
to allow the insertion of other obligatory non-imaging parts of the
radionuclide imaging camera, four fixation pins with threads 4 to
allow the fixation of the transparent window chamber with other
parts,
* * * * *